巨噬细胞糖代谢重编程在结核分枝杆菌感染中的研究进展

doi:10.19982/j.issn.1000-6621.20230266

摘要/Abstract

摘要：

巨噬细胞是参与先天性免疫的重要细胞,也是结核分枝杆菌感染的主要目标。研究发现,免疫细胞代谢重编程与其功能密切相关。在感染的早期阶段,巨噬细胞以M1极化为主,糖代谢方式从线粒体氧化磷酸化转变为有氧糖酵解(Warburg效应),促进炎性因子的分泌;在感染后期,巨噬细胞从有氧糖酵解转变为线粒体氧化磷酸化,从而抑制巨噬细胞促炎和抗菌反应。全面认识结核分枝杆菌感染期间巨噬细胞代谢与功能的关系有助于宿主导向疗法的发展。本文中,笔者对结核分枝杆菌感染期间巨噬细胞糖代谢重编程的相关研究进行了总结,以期为结核病的防治提供新思路。

关键词: 分枝杆菌,结核, 巨噬细胞, 免疫,细胞, 代谢, 糖酵解, 综述文献(主题)

Abstract:

Macrophages are important cells involved in innate immunity and also the main target of Mycobacterium tuberculosis infection. It was found that metabolic reprogramming of immune cells is closely related to their functions. In the early stage of infection, the main change of macrophages is M1 polarized, and the mode of glucose metabolism changes from mitochondrial oxidative phosphate to aerobic glycolysis (Warburg effect), which promotes the secretion of inflammatory factors; while in the late stages of infection, the mode of glucose metabolism of macrophages changes from aerobic glycolysis to mitochondrial oxidative phosphorylation, which inhibits macrophage proinflammatory and antimicrobial responses. A comprehensive understanding of the relationship between macrophage metabolism and function during Mycobacterium tuberculosis infection is help to the development of host directed therapy. In this article, the author summarized the related research on macrophage glycometabolism reprogramming during the infection of Mycobacterium tuberculosis, in order to provide new ideas for the prevention and treatment of tuberculosis.

Key words: Mycobacterium tuberculosis, Macrophages, Immunity, cellular, Metabolism, Glycolysis, Review literature as topic

中图分类号:

R392.12
R52

南岳, 龙美贞, 董玉慧, 王元智, 周向梅. 巨噬细胞糖代谢重编程在结核分枝杆菌感染中的研究进展[J]. 中国防痨杂志, 2023, 45(11): 1097-1102. doi: 10.19982/j.issn.1000-6621.20230266

Nan Yue, Long Meizhen, Dong Yuhui, Wang Yuanzhi, Zhou Xiangmei. Research progress on macrophage glucose metabolism reprogramming in Mycobacterium tuberculosis infection[J]. Chinese Journal of Antituberculosis, 2023, 45(11): 1097-1102. doi: 10.19982/j.issn.1000-6621.20230266

图/表 2

参考文献 48

[1]	Ahmad F, Rani A, Alam A, et al. Macrophage: A Cell With Many Faces and Functions in Tuberculosis. Front Immunol, 2022, 13: 747799. doi:10.3389/fimmu.2022.747799.
[2]	Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013, 496(7446): 445-455. doi:10.1038/nature12034.
[3]	Arish M, Naz F. Macrophage plasticity as a therapeutic target in tuberculosis. Eur J Immunol, 2022, 52(5): 696-704. doi:10.1002/eji.202149624.
[4]	Orecchioni M, Ghosheh Y, Pramod AB, et al. Corrigendum: Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS-) vs. Alternatively Activated Macrophages. Front Immunol, 2020, 11: 234. doi:10.3389/fimmu.2020.00234. pmid: 32161587
[5]	Muri J, Kopf M. Redox regulation of immunometabolism. Nat Rev Immunol, 2021, 21(6): 363-381. doi:10.1038/s41577-020-00478-8. pmid: 33340021
[6]	Makowski L, Chaib M, Rathmell JC. Immunometabolism: From basic mechanisms to translation. Immunol Rev, 2020, 295(1): 5-14. doi:10.1111/imr.12858. pmid: 32320073
[7]	Lunt SY, Vander Heiden MG. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol, 2011, 27: 441-464. doi:10.1146/annurev-cellbio-092910-154237. pmid: 21985671
[8]	Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol, 1927, 8(6): 519-530. doi:10.1085/jgp.8.6.519. pmid: 19872213
[9]	Mills CD, Kincaid K, Alt JM, et al. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol, 2000, 164(12): 6166-6173. doi:10.4049/jimmunol.164.12.6166. pmid: 10843666
[10]	Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res, 2015, 25(7): 771-784. doi:10.1038/cr.2015.68. pmid: 26045163
[11]	Van den Bossche J, O’Neill LA, Menon D. Macrophage Immunometabolism: Where Are We (Going)?. Trends Immunol, 2017, 38(6): 395-406. doi:10.1016/j.it.2017.03.001. pmid: 28396078
[12]	El Kasmi KC, Stenmark KR. Contribution of metabolic reprogramming to macrophage plasticity and function. Semin Immunol, 2015, 27(4): 267-275. doi:10.1016/j.smim.2015.09.001. pmid: 26454572
[13]	Palsson-Mcdermott EM, Curtis AM, Goel G, et al. Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab, 2015, 21(1): 65-80. doi:10.1016/j.cmet.2014.12.005. pmid: 25565206
[14]	Xie M, Yu Y, Kang R, et al. PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation. Nat Commun, 2016, 7: 13280. doi:10.1038/ncomms13280. pmid: 27779186
[15]	Millet P, Vachharajani V, McPhail L, et al. GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism. J Immunol, 2016, 196(6): 2541-2551. doi:10.4049/jimmunol.1501345. pmid: 26843329
[16]	Bae S, Kim H, Lee N, et al. α-Enolase expressed on the surfaces of monocytes and macrophages induces robust synovial inflammation in rheumatoid arthritis. J Immunol, 2012, 189(1): 365-372. doi:10.4049/jimmunol.1102073. pmid: 22623332
[17]	Meiser J, Krämer L, Sapcariu SC, et al. Pro-inflammatory Macrophages Sustain Pyruvate Oxidation through Pyruvate Dehydrogenase for the Synthesis of Itaconate and to Enable Cytokine Expression. J Biol Chem, 2016, 291(8): 3932-3946. doi:10.1074/jbc.M115.676817. pmid: 26679997
[18]	Board M, Humm S, Newsholme EA. Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. Biochem J, 1990, 265(2): 503-509. doi:10.1042/bj2650503. pmid: 2302181
[19]	Haschemi A, Kosma P, Gille L, et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab, 2012, 15(6): 813-826. doi:10.1016/j.cmet.2012.04.023. pmid: 22682222
[20]	Michelucci A, Cordes T, Ghelfi J, et al. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. Proc Natl Acad Sci U S A, 2013, 110(19): 7820-7825. doi:10.1073/pnas.1218599110.
[21]	Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature, 2013, 496(7444): 238-242. doi:10.1038/nature11986.
[22]	Mcfadden BA, Purohit S. Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera. J Bacteriol, 1977, 131(1): 136-144. doi:10.1128/jb.131.1.136-144.1977. pmid: 17593
[23]	Littlewood-Evans A, Sarret S, Apfel V, et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J Exp Med, 2016, 213(9): 1655-1662. doi:10.1084/jem.20160061.
[24]	Yunna C, Mengru H, Lei W, et al. Macrophage M1/M2 polarization. Eur J Pharmacol, 2020, 877: 173090. doi:10.1016/j.ejphar.2020.173090.
[25]	Rodríguez-Prados JC, Través PG, Cuenca J, et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol, 2010, 185(1): 605-614. doi:10.4049/jimmunol.0901698. pmid: 20498354
[26]	Mehrotra P, Jamwal SV, Saquib N, et al. Pathogenicity of Mycobacterium tuberculosis is expressed by regulating metabolic thresholds of the host macrophage. PLoS Pathog, 2014, 10(7): e1004265. doi:10.1371/journal.ppat.1004265.
[27]	Gleeson LE, Sheedy FJ, Palsson-McDermott EM, et al. Cutting Edge: Mycobacterium tuberculosis Induces Aerobic Glycolysis in Human Alveolar Macrophages That Is Required for Control of Intracellular Bacillary Replication. J Immunol, 2016, 196(6): 2444-2449. doi:10.4049/jimmunol.1501612. pmid: 26873991
[28]	Everts B, Amiel E, Huang SC, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKε supports the anabolic demands of dendritic cell activation. Nat Immunol, 2014, 15(4): 323-332. doi:10.1038/ni.2833. pmid: 24562310
[29]	Moon JS, Hisata S, Park MA, et al. mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP 3 Inflammasome Activation. Cell Rep, 2015, 12(1): 102-115. doi:10.1016/j.celrep.2015.05.046.
[30]	Shi L, Jiang Q, Bushkin Y, et al. Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection. mBio, 2019, 10(2): e02550-18. doi:10.1128/mBio.02550-18.
[31]	Nizet V, Johnson RS. Interdependence of hypoxic and innate immune responses. Nat Rev Immunol, 2009, 9(9): 609-617. doi:10.1038/nri2607. pmid: 19704417
[32]	Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab, 2003, 284(5): E855-E862. doi:10.1152/ajpendo.00526.2002.
[33]	Rider MH, Bertrand L, Vertommen D, et al. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis. Biochem J, 2004, 381(Pt 3): 561-579. doi:10.1042/BJ20040752. pmid: 15170386
[34]	Kang DD, Lin Y, Moreno JR, et al. Profiling early lung immune responses in the mouse model of tuberculosis. PLoS One, 2011, 6(1): e16161. doi:10.1371/journal.pone.0016161.
[35]	Koivunen P, Hirsilä M, Remes AM, et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem, 2007, 282(7): 4524-4532. doi:10.1074/jbc.M610415200. pmid: 17182618
[36]	Cardoso MS, Silva TM, Resende M, et al. Lack of the Transcription Factor Hypoxia-Inducible Factor 1α (HIF-1α) in Macrophages Accelerates the Necrosis of Mycobacterium avium-Induced Granulomas. Infect Immun, 2015, 83(9): 3534-3544. doi:10.1128/IAI.00144-15. pmid: 26099585
[37]	Evans WH, Karnovsky ML. The biochemical basis of phagocytosis. Ⅳ. Some aspects of carbohydrate metabolism during phagocytosis. Biochemistry, 1962, 1: 159-166. doi:10.1021/bi00907a024.
[38]	Rohde KH, Veiga DF, Caldwell S, et al. Linking the transcriptional profiles and the physiological states of Mycobacterium tuberculosis during an extended intracellular infection. PLoS Pathog, 2012, 8(6): e1002769. doi:10.1371/journal.ppat.1002769.
[39]	Jha AK, Huang SC, Sergushichev A, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity, 2015, 42(3): 419-430. doi:10.1016/j.immuni.2015.02.005. pmid: 25786174
[40]	Byles V, Covarrubias AJ, Ben-Sahra I, et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun, 2013, 4: 2834. doi:10.1038/ncomms3834. pmid: 24280772
[41]	Takeda N, O’Dea EL, Doedens A, et al. Differential activation and antagonistic function of HIF-α isoforms in macrophages are essential for NO homeostasis. Genes Dev, 2010, 24(5): 491-501. doi:10.1101/gad.1881410.
[42]	Lachmandas E, Beigier-Bompadre M, Cheng SC, et al. Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells. Eur J Immunol, 2016, 46(11): 2574-2586. doi:10.1002/eji.201546259. pmid: 27624090
[43]	Kim JS, Kim YR, Yang CS. Host-Directed Therapy in Tuberculosis: Targeting Host Metabolism. Front Immunol, 2020, 11: 1790. doi:10.3389/fimmu.2020.01790.
[44]	Cumming BM, Pacl HT, Steyn AJC. Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy. Front Cell Infect Microbiol, 2020, 10: 576596. doi:10.3389/fcimb.2020.576596.
[45]	Young C, Walzl G, Du Plessis N. Therapeutic host-directed strategies to improve outcome in tuberculosis. Mucosal Immunol, 2020, 13(2): 190-204. doi:10.1038/s41385-019-0226-5. pmid: 31772320
[46]	Rao M, Ippolito G, Mfinanga S, et al. Improving treatment outcomes for MDR-TB-Novel host-directed therapies and personalised medicine of the future. Int J Infect Dis, 2019, 80S: S62-S67. doi:10.1016/j.ijid.2019.01.039.
[47]	Jiang Q, Qiu Y, Kurland I J, et al. Glutamine Is Required for M1-like Polarization of Macrophages in Response to Mycobacterium tuberculosis Infection. mBio, 2022, 13(4): e0127422. doi:10.1128/mbio.01274-22.
[48]	Cumming BM, Addicott KW, Adamson JH, et al. Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages. Elife, 2018, 7: e39169. doi:10.7554/eLife.39169.

药物名称	作用靶点	药物效果
2-脱氧葡萄糖	己糖激酶	抑制糖酵解,减少白细胞介素-1β产生
3-溴丙酮酸	己糖激酶	抑制糖酵解
利托那韦	葡萄糖转运蛋白	抑制糖酵解
二氯乙酸盐	丙酮酸脱氢酶激酶	抑制糖酵解
FX-11	乳酸脱氢酶	抑制糖酵解,抑制细胞分裂及诱导型一氧化氮合酶的合成
TEPP-46	丙酮酸激酶	抑制缺氧诱导因子-1α,减少白细胞介素-1β产生
雷帕霉素	哺乳动物雷帕霉素靶蛋白	抑制糖酵解,增强抗菌活性
洛哌丁胺	哺乳动物雷帕霉素靶蛋白	抑制糖酵解,增强抗菌活性